David Cluck

Ceftolozane–tazobactam: A new-generation cephalosporin

PURPOSE The chemistry, pharmacokinetic and pharmacodynamic properties, efficacy, and safety of the recently introduced combination antimicrobial agent ceftolozane-tazobactam are reviewed. SUMMARY Ceftolozane-tazobactam (Zerbaxa, Cubist Pharmaceuticals) is a cephalosporin β-lactam and β-lactamase inhibitor marketed as a fixed-dose combination agent for the treatment of complicated urinary tract and intraabdominal infections. Its dosing and chemistry provide expansive antimicrobial coverage of gram-negative organisms, including Pseudomonas aeruginosa, and stable activity against many β-lactamases, as well as coverage of most extended-spectrum β-lactamase-producing organisms and some anaerobes. Ceftolozane-tazobactam is susceptible to hydrolysis by carbapenemase enzymes but is not affected by other resistance mechanisms such as efflux pumps and porin loss. Clinical trials demonstrated that combination treatment with ceftolozane-tazobactam plus metronidazole had efficacy comparable to that of levofloxacin in patients with complicated urinary tract infections, including pyelonephritis, and comparable to that of meropenem against complicated intraabdominal infections. A Phase III trial of ceftolozane-tazobactam versus meropenem for treatment of bacterial pneumonia, including ventilator-associated pneumonia, is underway. Adverse effects reported with ceftolozane-tazobactam use are comparable to those seen with other β-lactams (e.g., hypersensitivity, nausea, diarrhea, headache). Initially, ceftolozane-tazobactam may be reserved for targeted therapy against multidrug-resistant pathogens. CONCLUSION Ceftolozane-tazobactam is a new cephalosporin with enhanced activity against multidrug-resistant P. aeruginosa and other gram-negative pathogens.

Comparison of Postoperative Bleeding in Total Hip and Knee Arthroplasty Patients Receiving Rivaroxaban or Enoxaparin

Background: The Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) 1 to 4 trials compared rivaroxaban 10 mg daily with commonly used doses of enoxaparin and demonstrated similar rates of VTE and bleeding. Objective: To evaluate bleeding events between patients who received enoxaparin or rivaroxaban for prevention of venous thromboembolism (VTE) following total hip arthroplasty (THA) or total knee arthroplasty (TKA). Methods: Retrospective cohort that compared patients undergoing THA and TKA who received enoxaparin (enoxaparin) with those who received rivaroxaban (rivaroxaban) and also with those who received enoxaparin in the RECORD 1 to 4 trials (enoxaparin RECORD). The primary outcome was any postoperative bleeding, defined as a composite of major and clinically relevant nonmajor bleeding based on the definitions in the RECORD 1 to 4 trials. Results: There was a lower rate of any postoperative bleeding (2.2% vs 6.8%, P = 0.004) in patients who received enoxaparin compared with rivaroxaban, and bleeding rates between the enoxaparin group and the enoxaparin RECORD groups were similar (2.2% vs 2.5%, P = 0.085). Major bleeding in the enoxaparin group (0.2%) was not significantly different from that in the rivaroxaban group (1.4%, P = 0.12) or the RECORD group (0.2%, P = 0.93). Clinically relevant nonmajor bleeding was also lower in the enoxaparin group compared with the rivaroxaban group (2.0% vs 5.5%, P = 0.012). Conclusions: The use of enoxaparin for VTE prophylaxis following THA and TKA was associated with a lower rate of the primary outcome (any postoperative bleeding) compared with the use of rivaroxaban in a similar cohort of patients.

Isavuconazonium sulfate: a triazole prodrug for invasive fungal infections

To review the place in therapy of isavuconazole, the active metabolite of isavuconazonium sulfate, via a review of the available literature on drug chemistry, spectrum of activity, pharmacokinetic/pharmacodynamic profile and trials assessing clinical efficacy and safety.

Retrospective Evaluation of Postoperative Bleeding Events in Patients Receiving Rivaroxaban After Undergoing Total Hip and Total Knee Arthroplasty: Comparison with Clinical Trial Data.

Although data from the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) 1–4 trials have shown a similar postoperative bleeding risk between rivaroxban and enoxaparin in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA), anecdotal observations from local institutions have suggested that postoperative bleeding rates seemed higher in patients who received rivaroxaban than those reported in the RECORD trials. Thus, the objective of this pilot study was to assess postoperative bleeding events observed in clinical practice in patients receiving rivaroxaban after undergoing THA and TKA and to compare their results with those published in the RECORD trials.

A Therapeutic Perspective of Living with Human Immunodeficiency Virus/AIDS in 2017

Patients with human immunodeficiency virus (HIV)/AIDS live a far different life today compared with those who were infected in the 1980s and 1990s. Antiretroviral therapy has evolved from a once poorly tolerated, heavy pill burden to the availability of many once-daily single-tablet regimens. The improvements in therapy have necessitated the need to be cognizant of comorbidities as well as drug-drug interactions. Despite the tremendous advances in therapy, newer therapies are in the pipeline and continue to emerge, making care for patients burdened by HIV perhaps easier than it has ever been.

Stability of a pyrimethamine suspension compounded from bulk powder

Purpose. Development of a stability‐indicating high‐performance liquid chromatography (HPLC) method for pyrimethamine analysis, with subsequent application of that method to assess the 90‐day stability of a pyrimethamine suspension compounded from bulk USP‐grade pyrimethamine powder, is described. Methods. A stability‐indicating method of HPLC with ultraviolet detection specific to pyrimethamine was developed according to pharmacopeial recommendations and validated. The method was applied to investigate the stability of a 2‐mg/mL pyrimethamine suspension in a vehicle consisting of Ora‐Plus and Ora‐Sweet (Perrigo) over a period of 90 days. Three replicate test preparations were stored at room temperature or refrigerated at 4.3–5.2 °C, and samples were analyzed in duplicate immediately after preparation and on study days 1, 2, 4, 7, 10, 14, 21, 30, 48, 60, 75, and 90. Results. The 2‐mg/mL suspension of pyrimethamine in Ora‐Plus and Ora‐Sweet retained 90–110% of the labeled potency to 90 days at both temperature ranges. However, color changes in the samples stored at room temperature observed at day 60 indicated that a beyond‐use date less than 90 days from the preparation date should be specified when the suspension is to be stored at room temperature. Conclusion. The study demonstrated that USP‐grade pyrimethamine powder can be formulated as a 2‐mg/mL suspension in a vehicle of Ora‐Plus and Ora‐Sweet and is stable when stored at room temperature and when refrigerated, in amber plastic bottles, for 48 and 90 days, respectively.

Vancomycin plus nafcillin salvage for the treatment of persistent methicillin-resistant Staphylococcus aureus bacteremia following daptomycin failure: a case report and literature review

Background: Evidence supporting beta-lactam plus vancomycin synergy for methicillin-resistant Staphylococcus aureus (MRSA) continues to grow. Current in vivo evidence demonstrates that combination therapy is associated with shorter time to blood sterilization than vancomycin monotherapy. However, this combination has not been reported as salvage therapy for persistent MRSA bacteremia. Case report: We report a case of an 81-year-old male who was successfully treated with vancomycin plus nafcillin after failing vancomycin monotherapy, daptomycin monotherapy, and daptomycin plus gentamicin combination therapy. The patient originally presented with sepsis from a suspected urinary tract infection. Blood cultures drawn on days 1, 3, 5, 15, 19, 23, and 28 remained positive for MRSA despite multiple antimicrobial therapy changes. On day 29, therapy was changed to vancomycin plus nafcillin. Blood cultures drawn on day 32 remained negative. After 11 days, nafcillin was changed to piperacillin–tazobactam due to an infected decubitus ulcer. The combination was continued for 42 days after achieving blood sterility, 71 days after the patient originally presented. Evidence regarding salvage therapy for persistent bacteremia is sparse and is limited to case reports and case series. Conclusion: This case report supports that vancomycin plus an anti-staphylococcal beta-lactam combination should be further studied as salvage therapy for persistent MRSA bacteremia.

Extended infusion compared to standard infusion cefepime as empiric treatment of febrile neutropenia

Background Extended infusion (EI) dosing provides a longer time above the minimum inhibitory concentration, which is important for the clinical success of β-lactam antibiotics, especially for patients with impaired immunity. The aim of this study was to determine the feasibility and clinical impact of administering cefepime by EI as treatment of febrile neutropenia. Methods This was a prospective, randomized, comparative pilot study. All patients received cefepime 2 g IV every 8 h, with the first dose administered using a 30-min infusion. After the first dose, patients were randomized to receive cefepime over 30 min as a standard infusion (SI) or 3 h (EI). Patients were >18 years old with febrile neutropenia (neutrophil count <500 cells/mm3 and temperature >38.0ºC) and received chemotherapy or stem cell transplant as treatment for malignancy. Patients were excluded for the following: allergy to a cephalosporin, creatinine clearance (CrCl) < 50 mL/min, receipt of concurrent Gram-negative antimicrobial, sepsis, or solid tumor malignancy. The primary outcome was defervescence by 72 h. Secondary outcomes included time to defervescence, clinical success, in-hospital mortality, hospital length of stay, and need for additional antimicrobials. Main results Sixty-three patients were enrolled: 33 in the SI arm and 30 in the EI arm. The groups were similar with regard to age, gender, weight, estimated creatinine clearance, and duration of neutropenia. None of the patients in the EI arm withdrew due to practical complications of receiving EI cefepime. Twenty-three patients in the SI arm and 20 patients in the EI arm defervesced by 72 h (p = 0.99). There were no differences in secondary outcome measures; however, patients in the EI arm appeared to have defervesced more rapidly (median 19 vs. 41 h, p = 0.305). Conclusion Administration of cefepime by EI for the treatment of febrile neutropenia is feasible. Larger clinical trials are necessary to determine if EI cefepime imparts a clinical benefit in the treatment of febrile neutropenia.

Treatment strategies for persistent methicillin-resistant Staphylococcus aureus bacteraemia

Treatment of methicillin‐resistant Staphylococcus aureus (MRSA) bacteraemia is a long‐standing challenge to health care, often complicated by metastatic infections, treatment failure and mortality. When MRSA bacteraemia persists despite adequate initial treatment, current Infectious Diseases Society of America guidelines recommend evaluation and removal of possible sources of infection. In addition, a change in therapy may be considered. The objective of this review was to explore the therapeutic options for the treatment of persistent MRSA bacteraemia.

Comparison of perceived personality traits between the pharmacy residents admitted through the match or scramble process

INTRODUCTION The purpose of this study is to determine whether certain personality traits are as prominent in pharmacy practice residents who obtain positions through the post-Match process, previously referred to as the Scramble, as compared to residents who match directly with programs. METHODS Pharmacy residency program directors (RPDs) across the United States were asked to complete an electronic survey that gauged RPD perceptions of 13 personality traits commonly seen in pharmacy residents. RPDs were requested to separately evaluate residents who Scrambled and Matched to their respective programs. Exploratory factor analysis (EFA) was used to determine factor structure for the personality traits and to assess whether factors associate differentially between Matched and Scrambled residents. RESULTS A total of 1876 RPDs of post-graduate year one (PGY1), post-graduate year two (PGY2), and combined PGY1 and PGY2 pharmacy residency programs were contacted for study participation with a response rate of 21 percent. Demographic variables related to program type and number of residents per class were similar between Scrambled and Matched groups. The EFA identified two factors across 13 traits: we termed them as traditional traits and grit-like traits, and they significantly differed between the Scramble and Match groups. RPD perception of traditional traits (nine traits) were significantly higher in the Match group (p < 0.05), whereas perceived grit-like traits (four traits) were significantly higher in the Scramble group (p < 0.0001). CONCLUSION Residency candidates who Match versus candidates who Scramble are perceived to have unique and significantly different personality traits.